Transcription regulation by long non-coding RNAs: mechanisms and disease relevance

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(5), С. 396 - 415

Опубликована: Янв. 19, 2024

Язык: Английский

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Transcription factor interactions explain the context-dependent activity of CRX binding sites

PLoS Computational Biology, Год журнала: 2024, Номер 20(1), С. e1011802 - e1011802

Опубликована: Янв. 16, 2024

The effects of transcription factor binding sites (TFBSs) on the activity a cis-regulatory element (CRE) depend local sequence context. In rod photoreceptors, for (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but context that determines whether CRX contribute to activation or repression is not understood. To investigate context-dependent sites, we fit neural network-based models activities synthetic CREs composed photoreceptor TFBSs. revealed consistently make positive, independent contributions CRE activity, while negative homotypic interactions between cause multiple function as silencers. can be overcome by presence other TFBSs either interact cooperatively with positive activity. thus determined balance heterotypic interactions, TFBSs, interactions. Our findings explain observed patterns among genomic CRX-bound suggest may require diverse

Язык: Английский

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KSHV genome harbors both constitutive and lytically induced enhancers

Journal of Virology, Год журнала: 2024, Номер 98(6)

Опубликована: Май 2, 2024

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma-herpesvirus family and is a well-known human oncogenic virus. In infected cells, viral genome of 165 kbp circular DNA wrapped in chromatin. The tight control gene expression critical for latency, transition into lytic phase, development viral-associated malignancies. Distal cis -regulatory elements, such as enhancers silencers, can regulate position- orientation-independent manner. Open chromatin another characteristic feature enhancers. To systematically search enhancers, we cloned all open regions KSHV downstream luciferase tested their enhancer activity uninfected cells. A silencer was detected upstream latency-associated nuclear antigen promoter. Two constitutive were identified K12p-OriLyt-R ORF29 Intron regions, where tissue-specific enhancer. following promoters: OriLyt-L, PANp, ALTp, terminal repeats (TRs) acted lytically induced replication transcription activator (RTA), master regulator cycle, sufficient induce We propose that TRs span about 24 region serve “viral super-enhancer” integrates repressive effect (LANA) with activating RTA. Utilizing CRISPR activation interference techniques, determined connections between these regulated genes. described here provide an additional layer complex regulation herpesviruses. IMPORTANCE this study, performed systematic functional assay identify elements within herpesvirus, (KSHV). Similar other herpesviruses, presents both latent phases. Therefore, our assays during infection, under conditions. two one which seems be addition, four are responsive identified. Furthermore, major latency promoter locus. repeats, spanning kbp, seem like RTA transition.

Язык: Английский

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Super-enhancers in hepatocellular carcinoma: regulatory mechanism and therapeutic targets

Cancer Cell International, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 7, 2025

Super-enhancers (SEs) represent a distinct category of cis-regulatory elements notable for their robust transcriptional activation capabilities. In tumor cells, SEs intricately regulate the expression oncogenes and pivotal cancer-associated signaling pathways, offering significant potential cancer treatment. However, few studies have systematically discussed crucial role in hepatocellular carcinoma (HCC), which is one most common liver cancers with late-stage diagnosis limited treatment methods advanced disease. Herein, we first summarize identification intricate processes formation organization super-enhancers. Subsequently, delve into roles molecular mechanisms within framework HCC. Finally, discuss inhibitors targeting key SE-components effects on conclusion, this review meticulously encapsulates distinctive characteristics underscores context carcinoma, presenting novel perspective super-enhancers as emerging therapeutic targets

Язык: Английский

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Uncovering the whole genome silencers of human cells via Ss-STARR-seq

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 16, 2025

Silencers, the yin to enhancers' yang, play a pivotal role in fine-tuning gene expression throughout genome. However, despite their recognized importance, comprehensive identification of these regulatory elements genome is still its early stages. We developed method called Ss-STARR-seq directly determine activity silencers whole In this study, we applied human cell lines K562, LNCaP, and 293 T, identified 134,171, 137,753, 125,307 on genome-wide scale, respectively, function various cells cell-specific manner. Silencers exhibited substantial enrichment transcriptional-inhibitory motifs, including REST, demonstrated overlap with binding sites repressor transcription factors within endogenous environment. Interestingly, H3K27me3 did not reflect silencer but facilitated silencer's inhibitory expression. Additionally, have any significant histone markers at level. Our findings unveil that aspect-silencers only transition into enhancers diverse also achieve functional conversion insulators. Regarding biological effects, knockout experiments underscored redundancy specificity regulating proliferation. summary, study pioneers elucidation landscape cells, delineates global features, identifies specific influencing cancer critical regulation. Here, authors technique identify tens thousands cells. These possess unique epigenetic features are capable cellular phenotypes.

Язык: Английский

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An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 5, 2025

The role of non-coding regulatory elements and how they might contribute to tissue type specificity disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) a fatal, adult-onset, neurological disorder that characterized by extensive CNS demyelination. Most cases ADLD are caused tandem genomic duplications involving the lamin B1 gene (LMNB1) while small subset deletions upstream gene. Utilizing data from recently identified families carry LMNB1 but do not exhibit demyelination, patient tissues, CRISPR edited cell lines mouse models, we have silencer element lost in patients specifically targets expression oligodendrocytes. This consists CTCF binding sites mediate three-dimensional chromatin looping recruitment PRC2 transcriptional repressor complex. Loss identifies for causation. An oligodendrocyte-specific determines fatal widely expressed nuclear protein (Lamin B1) suggests

Язык: Английский

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A screen for regeneration-associated silencer regulatory elements in zebrafish

Developmental Cell, Год журнала: 2024, Номер 59(5), С. 676 - 691.e5

Опубликована: Янв. 29, 2024

Язык: Английский

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Uncovering the Contrasting Binding Behavior of Plant Flavonoids Fisetin and Morin Having Subsidiary Hydroxyl Groups (−OH) with HRAS1 and HRAS2 i-Motif DNA Structures: Decoding the Structural Alterations and Positional Influences

ACS Omega, Год журнала: 2023, Номер 8(33), С. 30315 - 30329

Опубликована: Авг. 7, 2023

Research on the interactions of naturally existing flavonoids with various noncanonical DNA such as i-motif (IM) structures is helpful in comprehending molecular basis binding mode well providing future direction for application and invention novel effective therapeutic drugs. IM have been identified prospective anticancer targets, are smaller molecules a variety health-promoting attributes, including activities. The extensive investigation comprising series techniques reveals contrasting behavior fisetin morin structures. We discovered that structural alterations hydroxyl groups located at different places aromatic rings influence flavonoid's reactivity. This minor alteration appears to be critical morin's capacity interact differentially HRAS1 HRAS2 DNA. Hence, an efficient ligand considered exploration opens up possibility employing strategy regulation gene expression cancerous cells. Our finding also flavonoid-mediated specific interaction while pointing toward tangible strategies drug discovery other essential cellular functions.

Язык: Английский

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DeepICSH: a complex deep learning framework for identifying cell-specific silencers and their strength from the human genome

Briefings in Bioinformatics, Год журнала: 2023, Номер 24(5)

Опубликована: Авг. 15, 2023

Silencers are noncoding DNA sequence fragments located on the genome that suppress gene expression. The variation of silencers in specific cells is closely related to expression and cancer development. Computational approaches exclusively rely information for silencer identification fail account cell specificity silencers, resulting diminished accuracy. Despite discovery several transcription factors epigenetic modifications associated with genome, there still no definitive biological signal or combination thereof fully characterize posing challenges selecting suitable signals their identification. Therefore, we propose a sophisticated deep learning framework called DeepICSH, which based multiple data sources. Specifically, DeepICSH leverages convolutional neural network automatically capture biologically relevant combinations strongly originating from diverse array signals. Furthermore, utilization attention mechanisms facilitates scoring visualization these combinations, whereas employment skip connections fusion multilevel features thereby empowering accurate within cells. Extensive experiments HepG2 K562 line sets demonstrate outperforms state-of-the-art methods Notably, introduce first time multi-omics classifying strong weak achieving favorable performance. In conclusion, shows great promise advancing study analysis complex diseases. source code available at https://github.com/lyli1013/DeepICSH.

Язык: Английский

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Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs

Nature Biomedical Engineering, Год журнала: 2024, Номер 8(7), С. 890 - 908

Опубликована: Май 22, 2024

Abstract The functions of non-coding regulatory elements (NCREs), which constitute a major fraction the human genome, have not been systematically studied. Here we report method involving libraries paired single-guide RNAs targeting both ends an NCRE as screening system for Cas9-mediated deletion thousands NCREs genome-wide to study their in distinct biological contexts. By using K562 and 293T cell lines embryonic stem cells, show that can redundant functions, many ultra-conserved silencer activity play essential roles growth cellular responses drugs (notably, element PAX6_Tarzan may be critical heart development, removing it from cells led defects cardiomyocyte differentiation). high-throughput screen, is compatible with single-cell sequencing, allow identification druggable NCREs.

Язык: Английский

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